Search results for "NONMEM"
showing 10 items of 19 documents
Population pharmacokinetic meta-analysis of individual data to design the first randomized efficacy trial of vancomycin in neonates and young infants.
2019
Abstract Objectives In the absence of consensus, the present meta-analysis was performed to determine an optimal dosing regimen of vancomycin for neonates. Methods A ‘meta-model’ with 4894 concentrations from 1631 neonates was built using NONMEM, and Monte Carlo simulations were performed to design an optimal intermittent infusion, aiming to reach a target AUC0–24 of 400 mg·h/L at steady-state in at least 80% of neonates. Results A two-compartment model best fitted the data. Current weight, postmenstrual age (PMA) and serum creatinine were the significant covariates for CL. After model validation, simulations showed that a loading dose (25 mg/kg) and a maintenance dose (15 mg/kg q12h if <…
A Bayesian Method for Predicting 5‐Fluorouracil Pharmacokinetic Parameters Following Short‐Term Infusion in Patients With Colorectal Cancer
2003
Abstract The objective of this study was to develop a population pharmacokinetic model and validate it using a Bayesian approach for predicting, a priori and a posteriori , the individual volume of distribution ( V d ) and clearance ( Cl ) of 5‐fluorouracil (5‐FU) given as short‐term intravenous infusion in weekly and multiple doses. Forty‐four patients were divided in group A (5‐FU weekly doses) including 27 patients with nonmetastatic colorectal adenocarcinoma treated with 450 mg/m 2 of 5‐FU, 1 day per week for 48 doses, plus oral levamisol (50 mg/8 h) for 3 days, every 15 days and group B (5‐FU multiple doses) including 17 patients with metastatic colorectal adenocarcinoma, receiving 5‐F…
Population pharmacokinetic parameters of vancomycin in critically ill patients.
2006
Summary Background: Intensive care unit patients are a highly heterogeneous population. Accurate dosing for this population requires characterization of the appropriate pharmacokinetic parameters. Objective: To estimate population pharmacokinetic parameters of vancomycin (VAN) in adult critically ill patients and to establish the predictive performance of the resulting model. Patients and method: Fifty critically ill patients with suspected or documented infection with VAN-sensitive micro-organisms were included. Thirty patients and 234 serum concentration–time sets obtained during clinical routine monitoring were used to estimate the pharmacokinetic parameters (group A). An open bicompa…
Semi-physiologic model validation and bioequivalence trials simulation to select the best analyte for acetylsalicylic acid
2015
Abstract The objective of this paper is to apply a previously developed semi-physiologic pharmacokinetic model implemented in NONMEM to simulate bioequivalence trials (BE) of acetyl salicylic acid (ASA) in order to validate the model performance against ASA human experimental data. ASA is a drug with first-pass hepatic and intestinal metabolism following Michaelis–Menten kinetics that leads to the formation of two main metabolites in two generations (first and second generation metabolites). The first aim was to adapt the semi-physiological model for ASA in NOMMEN using ASA pharmacokinetic parameters from literature, showing its sequential metabolism. The second aim was to validate this mod…
Computer simulations for bioequivalence trials: Selection of analyte in BCS class II and IV drugs with first-pass metabolism, two metabolic pathways …
2018
A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of KM Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of t…
Kinetic modelling of passive transport and active efflux of a fluoroquinolone across Caco-2 cells using a compartmental approach in NONMEM.
2005
The purpose was to develop a general mathematical model for estimating passive permeability and efflux transport parameters from in vitro cell culture experiments. The procedure is applicable for linear and non-linear transport of drug with time,10 or10% of drug transport, negligible or relevant back flow, and would allow the adequate correction in the case of relevant mass balance problems. A compartmental kinetic approach was used and the transport barriers were described quantitatively in terms of apical and basolateral clearances. The method can be applied when sink conditions are not achieved and it allows the evaluation of the location of the transporter and its binding site. In this …
Validación de Procedimientos Poblacionales mediante Convolución para el Establecimiento de Correlaciones In Vitro-In Vivo
2018
Para desarrollar medicamentos que sean efectivos y seguros es necesario conocer su comportamiento tanto in vitro como in vivo. Uno de los desafíos en la investigación biofarmacéutica es correlacionar la información de liberación in vitro de un fármaco con los perfiles plasmáticos in vivo. Por lo tanto, durante los últimos años se ha incrementado el uso de modelos matemáticos que sean capaces de predecir el comportamiento in vivo de un fármaco a través de los datos de disolución in vitro, es decir, correlaciones in vitro - in vivo (IVIVC). Las IVIVC pueden acortar la duración del desarrollo de los medicamentos, así como reducir el gasto y mejorar la calidad del producto. El principal objetiv…
Computer simulations for bioequivalence trials: selection of analyte in BCS drugs with first-pass metabolism and two metabolic pathways.
2010
The objective of this work is to use a computer simulation approach to define the most sensitive analyte for in vivo bioequivalence studies of all types of Biopharmaceutics Classification System (BCS) drugs undergoing first-pass hepatic metabolism with two metabolic pathways. A semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Four BCS classes (from Class I to IV) of drugs, with three possible saturation scenarios (non-saturation, saturation and saturation of only the major route of metabolism), two (high or low) dose schemes, and six types of pharmaceutical quality for the drug products were simulated. The number of investigated scenarios was 144 (4 × 3…
Computer simulations of bioequivalence trials: selection of design and analyte in BCS drugs with first-pass hepatic metabolism: linear kinetics (I).
2008
Modeling and simulation approaches are useful tools to assess the potential outcome of different scenarios in bioequivalence studies. The aim of this study is to propose a new and improved semi-physiological model for bioequivalence trial simulations and apply it for all BCS (Biopharmaceutic Classification System) drug classes with non-saturated first-pass hepatic metabolism. The semi-physiological model was developed in NONMEM VI to simulate bioequivalence trials. Parent drug and metabolite levels for both reference and test were simulated. Eight types of drugs (with high or low permeability and high or low solubility (class I to IV) and high or low intrinsic clearance) were considered in …
A multilevel object-oriented modelling methodology for physiologically-based pharmacokinetics (PBPK): Evaluation with a semi-mechanistic pharmacokine…
2019
Abstract Background and objective The aims of this study are (i) to assess the predictive reliability of the physiologically based software PhysPK versus the well-known population approach software NONMEM for the cited semi-mechanistic PK model, (ii) to determine whether these modelling approaches are interchangeable and (iii) to compare acausal with causal modelling approaches in the framework of semi-mechanistic PK models. Methods A semi-mechanistic model was proposed, which assumed oral administration of a solid dosage form with a peripheral compartment and two active metabolites. The model incorporates intestinal transit, dissolution limited by solubility, variable efflux transporter ex…